P1010: RUXOLITINIB IN MYELODEPLETIVE MYELOFIBROSIS: RESPONSE, TOXICITY, AND OUTCOME
Authors: F. Palandri, D. Bartoletti, M. Breccia, G. Auteri, E. M. Elli, M. M. Trawinska, N. Polverelli, M. Tiribelli, G. Benevolo, A. Iurlo, A. Tieghi, F. H. Heidel, G. Caocci, E. Beggiato, G. Binotto, F. Cavazzini, M. Miglino, C. Bosi, M. Crugnola, M. Bocchia, B. Martino, N. Pugliese, A. D. Romagnoli, C. Mazzoni, L. Scaffidi, A. Isidori, D. Cattaneo, M. Krampera, F. Pane, D. Cilloni, G. Semenzato, R. M. Lemoli, A. Cuneo, E. Abruzzese, N. Vianelli, M. Cavo, M. Bonifacio, G. A. Palumbo
Journal: HemaSphere (2022)

Background: Around 30% of Myelofibrosis (MF) either primary (PMF) or secondary to polycythemia vera/essential thrombocythemia (SMF) may present a myelodepletive phenotype (MyD) (ie, thrombocytopenia, leukopenia, anemia). Pts with MyD MF represent a challenging population, as prognosis is poorer compared to pts with myeloproliferative (MyP) MF and therapeutic options, including the JAK1/2 inhibitor ruxolitinib (RUX), are limited or must be given at reduced doses. Aims: In light of the upcoming new drugs that may be used in MyD MF, we explored prognostic correlates of MyD phenotype in RUX-treated MF pts. Methods: After IRB approval, the “RUX-MF” retrospective real-world study collected 801 chronic phase MF pts treated with RUX in 26 Hematology Centers. MyD was defined as: WBC <4×109/L and/or Hb <11/<10 g/dL (males/females) and/or PLT <100×109/L with no increase of other blood cells (WBC >15×109/L, Hb >16.5/>16 g/dL in males/females, Plt >450×109/L). 219 (27.3%) had a MyD MF, including 140 (17.5%) PMF and 79 (9.8%) SMF. Spleen and symptoms response (SR/SyR) were defined according to IWG-MRT criteria. NGS mutational analysis was available for 167 pts. Results: In multivariable analysis (MVA), PMF diagnosis (p=0.001) and unfavorable karyotype (p=0.01) confirmed their significant association with MyD. In PMF pts, MyD was due to leukopenia, anemia and thrombocytopenia in 7.1%, 52.2% and 9.3%, respectively; in SMF, corresponding figures were 5%, 51.9% and 11.4%. Two or more cytopenias were found in 31.4% and 31.7% of PMF and SMF patients, respectively. In MVA, lower peripheral blast count (p=0.03), higher TSS (p=0.04) and BM fibrosis grade ≥2 (p=0.03) confirmed their association with MyD in PMF pts. In univariate/MVA, MyD SMF patients were more likely to have higher peripheral blast count (p=0.003/p=0.04), a higher MYSEC-PM risk (p<0.001/p=0.001), and to be triple negative (p=0.005/0.03). RUX starting, median at 3 months, and median overall dose was more frequently ≤10 mg BID in MyD than in MyP pts (44.9% vs 67.5%, p<0.001; 39.5% vs 59.9%, p<0.001; 34.9% vs 57.3%, p<0.001, respectively). This was confirmed also in PMF and SMF separately. The rate of SR was comparable in MyD and MyP patients. However, SR at 3 and 6 months was lower in pts with PLT<100 x 109/l (p=0.02). In SMF, MyD pts had lower rates of SR (10.8% vs 28.0% at 3 mos, p=0.004; 20.0% vs 33.1% at 6 mos, p=0.05). SyR was significantly lower in MyD MF (51.9% vs 62.5% in MyP at 3 mos, p=0.01; 59.8% vs 71.0% at 6 mos, p=0.008). In particular, anemia and thrombocytopenia were significantly associated with lower SyR. After a median RUX exposure of 2.3 yrs (0.1-12.6), 364 (45.4%) pts stopped RUX, 110 (13.7%) had a blast phase and 366 (45.7%) died. After competing risk analysis, the cumulative incidence of RUX discontinuation was higher in MyD MF patients overall (p<0.001), only PMF (p=0.03) and only SMF (p<0.001) (Fig.1a). Incidence of RUX stop was significantly higher in MyD patients with ≥2 cytopenias (p=0.03). Leukemia-free survival was not influenced by MyD/MyP phenotype (Fig.1b). In Cox regression analysis adjusted for DIPSS score, OS was significantly shorter in MyD vs MyP MF (median, 4.5 vs 5.7 yrs; p=0.03) (Fig.1c). This was confirmed considering only SMF patients (p=0.02). Image:Summary/Conclusion: MyD phenotype is associated with baseline high-risk clinical and molecular features, with lower responses to RUX, particularly in case of low PLT count, and higher risk of drug discontinuation and death. Newer strategies are warranted in this setting.